international seminar "hiv vaccine research: ethical and regulatory issues" 4-5 october...

International Seminar "HIV Vaccine Research: Ethical and Regulatory Issues"

4-5 October 2006, Brasilia, Brazil

" Scientific, Regulatory and Ethical Issues in

HIV Vaccine Research: the WHO Perspective"

Dr Saladin Osmanov

WHO-UNAIDS HIV Vaccine Initiative

World Health Organization

Geneva, Switzerland

WHO-UNAIDS HIV Vaccine Initiative 2

25 years since the first report of the first AIDS cases25 years since the first report of the first AIDS cases

June 1981:

Official registration of the first AIDS cases in USA

November 1983 – May 1984

Identification of the human immunodeficiency virus (HIV) as a causative agent of AIDS

October-November 1987

The first HIV vaccine trial started


Number of people living with HIV by the end of 2005 Number of people living with HIV by the end of 2005

Total: 40.3 (36.7 – 45.3) million

Western & Central Europe

720 000720 000[570 000 – 890 000][570 000 – 890 000]

North Africa & Middle East510 000510 000

[230 000 – 1.4 million][230 000 – 1.4 million]

Sub-Saharan Africa25.8 million25.8 million

[23.8 – 28.9 million][23.8 – 28.9 million]

Eastern Europe & Central Asia1.6 million 1.6 million

[990 000 – 2.3 million][990 000 – 2.3 million]

South & South-East Asia7.4 million7.4 million[4.5 – 11.0 million][4.5 – 11.0 million]

Oceania74 00074 000

[45 000 – 120 000][45 000 – 120 000]

North America1.2 million1.2 million

[650 000 – 1.8 million][650 000 – 1.8 million]

Caribbean300 000300 000

[200 000 – 510 000][200 000 – 510 000]

Latin America1.8 million1.8 million

[1.4 – 2.4 million][1.4 – 2.4 million]

East Asia870 000870 000

[440 000 – 1.4 million][440 000 – 1.4 million]


The HIV pandemic continues its accelerated spread at a rate of 14.000 – 15.000 cases of HIV infection every day

and 5.000.000 cases every year

The HIV pandemic continues its accelerated spread at a rate of 14.000 – 15.000 cases of HIV infection every day

and 5.000.000 cases every year

More than 95% of cases in developing countries

More than 40% of cases among women

More than 50% of cases among young people of 15-24 years of age

Up to 10% of cases among children younger than 15 years


Scientific, Regulatory and Ethical Issues in relation to HIV/AIDS Vaccine R & D

Scientific, Regulatory and Ethical Issues in relation to HIV/AIDS Vaccine R & D

A critical need for a safe, effective and affordable HIV vaccine drives a push for moving multiple vaccine candidates into clinical trials

If some of the trails are successful, there would be a need to secure license from local National Regulatory Authorities (NRAs)

To facilitate this decision making by NRAs there is a need to develop regulatory frameworks for HIV vaccines addressing multiple scientific, ethical and logistical challenges related to the preparation and conduct of HIV vaccine trials


Scientific Challenges for HIV Vaccine R & DScientific Challenges for HIV Vaccine R & D

- Genetic variation of HIV

- Correlates of immune protection

- Role and value of animal models

- Multiple vaccination strategies to be explored


The current international classification and nomenclature of HIV

The current international classification and nomenclature of HIV

HIV

Types: HIV-1, HIV-2

Groups: M, N, O

Subtypes: A-D, F-H, J, K

Intersubtype recombinants:

Curculating Recombinant Forms:

- CRF01_AE, CRF02_AG, etc.

- Unique Recombinant Forms


The global proportion of HIV infections caused by different HIV Subtypes and CRFs by 2005

The global proportion of HIV infections caused by different HIV Subtypes and CRFs by 2005


Distribution of HIV Subtypes and CRFs by 2005Distribution of HIV Subtypes and CRFs by 2005


Impact of HIV-1 Genetic Variability on the Development and Evaluation of HIV vaccines


Systematic genetic characterization of HIV-1 strains has

proven to be a valuable tool for:

- Tracking the dynamics and spread of genetic subtypes of HIV-1 and CRFs on a global basis.

- Generation of key data to provide rationale for matching the locally prevalent HIV strains with vaccine candidates.

- Provision of critical information for improved diagnostic and treatment strategies




However, a number of scientific unknowns remain to be addressed:

- The molecular epidemiology of HIV-1 is characterized by increasingly complex patterns with a clear shift from pure subtypes to recombinant strains.

- The present HIV-1 classification is becoming more and more obsolete, in particular due to the fact that it does not directly reflect/predict biology and immunology of the virus.

- Relevance of genetic subtypes and CRFs of HIV-1 for vaccine protection needs to be critically assessed by appropriately designed vaccine efficacy trials.


Potential scenarios of "matched" vs "mismatched" trials in Brazil

Potential scenarios of "matched" vs "mismatched" trials in Brazil

1. Complete match between vaccine specificity and a prevalent HIV-1subtype in a study population, e.g. subtype B candidate vaccine among MSM

2. Complete mismatch, e.g. subtype E candidate vaccine among both MSM and IDU

3. Partial match, e.g. subtype C or subtype B candidate vaccine in IDU population in Brazil


Correlates of vaccine induced immune protectionCorrelates of vaccine induced immune protection

В-cell humoral immunity

- Binding and neutralizing AB

Т-cell mediated immunity

- Cytotoxic lymphocytes (CD8+ CTLs)

- CD4+Т-helper cells

- Cytokine networks and innate immunity

- Immune memory

Mucosal immunity

Combination of all above

- Type and quality of immune responses

CTL


Potential end-points for HIV vaccine efficacyPotential end-points for HIV vaccine efficacy


Efficacy issuesEfficacy issues

Prevention of infection/disease

- Sterilizing immunity

- Modification of virus load

- Decrease infectiousness (transmission)

- Better response to ARV treatment

Level of efficacy

Efficacy against different virus subtypes

Efficacy in different populations– Different routes of transmission

– Different host background: genetic, age, behavioural, social, etc.


Different HIV vaccine strategiesDifferent HIV vaccine strategies

Peptides

Recombinant proteins

DNA vaccines

Vectored vaccines (virus or bacterial vectors)

Prime-boost combinations

Attenuated vaccines

Whole Inactivated vaccines


Role and Value of Animal ModelsRole and Value of Animal Models

The currently available animal models do not provide for go/no-go check point in pre-clinical research. Important questions need to be resolved, e.g.:

- Which model mimics more closely the HIV infection in humans?

- Different models produce controversial results. Which are most appropriate?

- Need for key improvements to model• Creating a more human exposure model• Repetitive low dose vaginal challenges


Evolution of strategic approaches to HIV vaccine R & D

Evolution of strategic approaches to HIV vaccine R & D

First generation of HIV vaccines (1987-1990 )

- Induction of neutralizing/binding AB

- HIV-1 envelope derived antigens (rgp160, rgp120, peptides)

Second generation of HIV vaccines ( 1990-2000)

- Induction of T-cell immunity (CD8+, CD4+/CTL)

- Vectored and DNA vaccines

- "Prime-boost" combinations

Third generation of HIV vaccines (2000-present)

- Stimulation of more potent and broad spectrum of anti-HIV responses

- Candidate vaccines derived on functionally important epitopes based on the globally prevalent HIV strains (subtypes A, B, C, D, CRF01_AE,etc.)


Major lessons learnt from phase I/II clinical trials with the first and second generation of HIV vaccines in 1987-2003

Major lessons learnt from phase I/II clinical trials with the first and second generation of HIV vaccines in 1987-2003

More than 30 vaccine candidates tested in phase I/II trials

With participation of more than 7,000 HIV-negative volunteers

Trials were conducted both in developed and developing countries, including USA, Europe, Thailand, Brazil, Uganda, Kenya, Cuba, China

Practically, all vaccine candidates were highly safe. However, immunogenicity and duration of immune responses were far less than optimal, in particular with vaccines targeting T-cell immunity


Lessons learnt from the first phase III efficacy trials

Lessons learnt from the first phase III efficacy trials

rgp120 BB (AIDSVAX B/B) (VaxGen)– USA, Canada, the Netherlands– 5.418 volunteers, mostly MSM with only a small control group

involving women with high risk for HIV– Start: June 1998– Completed: February 2003

rgp120 BE (AIDSVAX B/E) (VaxGen)– Thailand – 2.545 volunteers (IDUs) – Start: March 1999– Completed: January 2004

Don FrancisPhil Berman


Results from the first HIV vaccine phase III trialsResults from the first HIV vaccine phase III trials

Both phase III trials did not show any significant level of efficacy.

However, these trials have also demonstrated that:

- Phase III trials can be successfully conducted in high risk volunteers, including IVDUs and MSM

- Large numbers of volunteers can be recruited and followed up

- Trial endpoints occur throughout the trial and not just clustered in the first half of the trial

- Behavioural counseling is effective and no evidence of increased risk in either IVDUs or MSMs, but residual risk group persists

- Attention needs to be directed to adequate recruitment of women and minorities in large efficacy trials


The third on-going phase III trial in ThailandThe third on-going phase III trial in Thailand

rgp120 BE (VaxGen) + ALVAC (Pasteur Merieux)

– 16,000 volunteers– Expected efficacy: 50%

protection agains HIV infection

– Or control of viral replication and reduced viral load set point

– Start: September 2003– End: January 2008

Upper North

Lower North

Northeast

South

Central Chon Buri

Rayong


Challenges for Generation of Functional Humoral Immunity

Challenges for Generation of Functional Humoral Immunity

Renewed, concentrated and cooperative effort towards the development of immunogens capable of inducing functional humoral immunity

– Not just binding antibody– New effort in increasing sensitivity, specificity, and

reproducibility of neutralization assays– Expanded work in understanding native gp160 - structure

pre/post binding and stability– Increasing preclinical focus on immunogens inducing

functional Ab (generation of ADCC, neutralization of primary isolates)


New generation of HIV vaccinesNew generation of HIV vaccines

Recombinant proteins/peptides

Lipopeptides

Gp120/gp140 (subtypes A,B,C, CRFs, etc.)

Oligomeric proteins Env gp140 (subtypesA,B,C, CRFs and others)

Regulatory proteins of HIV (e.g.,Tat, Nef)


Challenges for Targeting Cellular ImmunityChallenges for Targeting Cellular Immunity

Establish baseline anti-vector immunity

– Need strategies to overcome pre-existing immunity

Establish gold standard to measure cellular immunity (CD8+ T cells)

– Increased sensitivity of assays must be linked to functional standards or validated through animal model protection studies

Improve assessment of CD4+ T cell function

Need to standardize lab platforms for immune assessment around the globe

– SOPs– Tech transfer– Specimen processing, storage and shipment


Progress in addressing issues in relation to: HIV Variability and Improving Cellular Immunogenicity

Progress in addressing issues in relation to: HIV Variability and Improving Cellular Immunogenicity

Pox Vectors

Canary Pox (A, B, E)

Fowl Pox (B, E)

MVA (A,B,C,D,E,CRF02) SAAVI VRC Aaron Diamond Emory Oxford Therion Eurovac USMHRPNYVAC, Tan/Tan Eurovacc

Pox Vectors

Canary Pox (A, B, E)

Fowl Pox (B, E)

MVA (A,B,C,D,E,CRF02) SAAVI VRC Aaron Diamond Emory Oxford Therion Eurovac USMHRPNYVAC, Tan/Tan Eurovacc

DNAsWyeth (B)

Emory (CRF02,B,C)

U of Penn (A,C,D,E)

Eurovacc(C)

Oxford (A)

SAAVI (C)

Karolinska (A,D)

Aaron Diamond(C)

Chiron (C)

DNAsWyeth (B)

Emory (CRF02,B,C)

U of Penn (A,C,D,E)

Eurovacc(C)

Oxford (A)

SAAVI (C)

Karolinska (A,D)

Aaron Diamond(C)

Chiron (C)

Other Vectors

Salmonella (B,C) WRAIR IHV

Adenovirus VRC (A,B,C) Merck (B)

Semliki Forest (A,B,C)

VEE (C gag) SAAVIAlphavax

VSV YaleAAV JohnsonMeaslesPolio

Simbis Virus Chiron

Other Vectors

Salmonella (B,C) WRAIR IHV

Adenovirus VRC (A,B,C) Merck (B)

Semliki Forest (A,B,C)

VEE (C gag) SAAVIAlphavax

VSV YaleAAV JohnsonMeaslesPolio

Simbis Virus Chiron


Need to conduct multiple efficacy trials,especially in developing countries

Need to conduct multiple efficacy trials,especially in developing countries


Current Challenges for HIV Vaccine R & DCurrent Challenges for HIV Vaccine R & D

Clinical trial issues

- Numerous clinical trials need to be conducted in developed and developing countries

- Criteria to move forward candidate vaccines through phase I-III trials and novel approached to the trial design (IIa, IIb trials ?)

- Definition of trial end-points and expected vaccine effects

- Trial to determine vaccine efficacy in diverse populations: ethnicity, gender and age, with a special focus on women and adolescents



Regulatory and ethical aspects

- Production of candidate vaccines for clinical trials (GMP)

- Immunogenicity and potency measurement

- Safety monitoring

- Regulatory and ethical review, approval and oversight

- Ensuring the required standards (GCP, GLP)

- Access to care and treatment

- Potential licensing and immunization strategies



Clinical trial site development

- Need for comprehensive site development in developing countries and integration of HIV vaccine research into national strategic planning, with a special focus on capacity building, training and infrastructure development

- Broad and effective community involvement

Advocacy and policy development

- Addressing issues of future access to and public health use of HIV vaccines (not only financial aspects)

- Cooperation and the development of regional frameworks (e.g. AAVP)

- Novel paradigms for international collaboration and partnerships (Global HIV Vaccine Enterprise)


Logistical Issues related to the conduct of HIV vaccines trials in developing countries

Logistical Issues related to the conduct of HIV vaccines trials in developing countries

Availability of cohorts Availability of cohorts Social behaviour expertiseSocial behaviour expertise

Government Government willingness willingness

& commitment & commitment

Epidemiology Epidemiology Virus MonitoringVirus Monitoring

Community Community involvementinvolvement

Public (media) attentionPublic (media) attention

Regulatory & Regulatory & Ethical Ethical

FrameworksFrameworksScientific Scientific

infrastructureinfrastructure

Clinical trial and Clinical trial and Laboratory expertiseLaboratory expertise

Data managementData management

National National CapacityCapacity Building Building

--

National National CapacityCapacity Building Building

--

InternationInternational al

collaboraticollaboration on

InternationInternational al

collaboraticollaboration on


National AIDS Vaccine Plans and Strategies National AIDS Vaccine Plans and Strategies

Initiated in 1992 in Brazil, Thailand and Uganda.

Continued in several other countries.

Facilitate trials by describing policies, approval mechanisms, and research priorities.

Brazil: Second generation (2000)


New Generation of National AIDS Vaccine Plans/Strategies

TECHNICAL COMPONENTS

Virology EpidemiologySocio/

behaviouralClinical

trialsMedia/

PR Etc

NORMATIVE FRAMEWORKPolitical Legal Regulatory LogisticalEthical

SUPPORTING ENVIRONMENT Community

supportHIV/AIDSPrevention

Access to care, incl. ART

Infrastructure/human resources

Etc


Supporting AIDS vaccine activities in developing countries Supporting AIDS vaccine activities in developing countries

Ethics Guidelines Media Handbook


Addressing future introduction, cost-effectiveness and delivery of HIV vaccines

Addressing future introduction, cost-effectiveness and delivery of HIV vaccines

Considerations with regard to different scenarios:

- Introduction of the first "imperfect" HIV vaccines (sub-optimal efficacy, impact of genetic variability, different modes of transmission, multiple host and population factors)

Development of cost-effective and targeted interventions and immunization strategies (women, adolescents, high-risk groups), as part of the overall HIV prevention, treatment and care programmes

Production of sufficient quantities and affordable price


The African AIDS Vaccine Programme (AAVP)

The African AIDS Vaccine Programme (AAVP)

The AAVP is a network of African scientists and community, working together to promote and facilitate HIV vaccine research and evaluation in Africa, through capacity-building and regional and international collaboration (“the voice of Africa”).

Activities being developed and implemented through six thematic working groups:

– Advocacy, information and resource mobilization.– Biomedical sciences (laboratory and clinical).– Population studies (Epidemiology and Socio-Behavioural

issues).– Ethics, Law and Human Rights.– National Strategic Planning.– Community.


50 volunteers1 country

20002000

400 volunteers8 countries15 trial sites

> 4 000 volunteers? 12 countries

20062006

Increasing participation of African countries in Increasing participation of African countries in HIV vaccine trialsHIV vaccine trials

20082008

>10 000 volunteers

20120100


Klausner et al. Science 2003, 300:2036-2039Klausner et al. Science 2003, 300:2036-2039


New Opportunities, Evolving Partnerships,Commitment and Collaboration and New Paradigms

New Opportunities, Evolving Partnerships,Commitment and Collaboration and New Paradigms

Unity of Mission– Development of a globally effective HIV vaccine

Shared vision– Concentrated and comprehensive focus on developing

countries in sub-Saharan Africa, Asia and Latin America

Unique opportunity but new challenges to all sponsors– Coordinate– Optimize - site development– Share - knowledge, personnel, sites, safety data– Unify - single immunologic evaluative platform

international seminar "hiv vaccine research: ethical and regulatory issues" 4-5 october...

Documents

affordable hiv vaccine

impact of hiv

nomenclature of hiv

hiv pandemic

cases of hiv infection

conduct of hiv vaccine

distribution of hiv

different hiv subtypes